Department of Clinical Nutrition, Chengdu Fifth People's Hospital, Chengdu, Sichuan, China.
Department of Nutrition, Food Safety and Toxicology, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China.
Mutagenesis. 2022 Oct 26;37(3-4):213-225. doi: 10.1093/mutage/geac012.
Two prototypical genotoxicants, benzo[a]pyrene (B[a]P) and colchicine (COL), were selected as model compounds to deduce their quantitative genotoxic dose-response relationship at low doses in a multi-endpoint genotoxicity assessment platform. Male Sprague-Dawley rats were treated with B[a]P (2.5-80 mg/kg bw/day) and COL (0.125-2 mg/kg bw/day) daily for 28 days. The parameters included were as follows: comet assay in the peripheral blood and liver, Pig-a gene mutation assay in the peripheral blood, and micronucleus test in the peripheral blood and bone marrow. A significant increase was observed in Pig-a mutant frequency in peripheral blood for B[a]P (started at 40 mg/kg bw/day on Day 14, started at 20 mg/kg bw/day on Day 28), whereas no statistical difference for COL was observed. Micronucleus frequency in reticulocytes of the peripheral blood and bone marrow increased significantly for B[a]P (80 mg/kg bw/day on Day 4, started at 20 mg/kg bw/day on Days 14 and 28 in the blood; started at 20 mg/kg bw/day on Day 28 in the bone marrow) and COL (started at 2 mg/kg bw/day on Day 14, 1 mg/kg bw/day on Day 28 in the blood; started at 1 mg/kg bw/day on Day 28 in the bone marrow). No statistical variation was found in indexes of comet assay at all time points for B[a]P and COL in the peripheral blood and liver. The dose-response relationships of Pig-a and micronucleus test data were analyzed for possible point of departures using three quantitative approaches, i.e., the benchmark dose, breakpoint dose, and no observed genotoxic effect level. The practical thresholds of the genotoxicity of B[a]P and COL estimated in this study were 0.122 and 0.0431 mg/kg bw/day, respectively, and our results also provided distinct genotoxic mode of action of the two chemicals.
选择两种典型的遗传毒性物质苯并[a]芘（B[a]P）和秋水仙碱（COL）作为模型化合物，在多终点遗传毒性评估平台上推断它们在低剂量下的定量遗传毒性剂量-反应关系。雄性 Sprague-Dawley 大鼠每天用 B[a]P（2.5-80mg/kg bw/天）和 COL（0.125-2mg/kg bw/天）处理 28 天。参数包括：外周血和肝脏的彗星试验、外周血的 Pig-a 基因突变试验和外周血和骨髓的微核试验。B[a]P（第 14 天开始 40mg/kg bw/天，第 28 天开始 20mg/kg bw/天）外周血中 Pig-a 突变频率显著增加，而 COL 则无统计学差异。B[a]P（第 4 天外周血网织红细胞和骨髓微核频率显著增加，第 14 天和第 28 天 80mg/kg bw/天；第 28 天 20mg/kg bw/天）和 COL（第 14 天开始 2mg/kg bw/天，第 28 天 1mg/kg bw/天）外周血和骨髓微核频率显著增加。B[a]P 和 COL 在所有时间点在外周血和肝脏的彗星试验指标均无统计学变化。使用三种定量方法，即基准剂量、断点剂量和无观察到的遗传毒性作用水平，对 Pig-a 和微核试验数据的剂量-反应关系进行了分析，以确定可能的起点。本研究估计 B[a]P 和 COL 的遗传毒性实际阈值分别为 0.122 和 0.0431mg/kg bw/天，结果还提供了这两种化学物质的不同遗传毒性作用模式。
